Abstract: A combination of approaches – gene mapping, biomarker analysis, and studies of signal transduction – has helped to clarify the mechanisms of age-related change in mouse immune status and the implications of immune aging for late-life disease. Mapping studies have documented multiple quantitative trait loci (QTL) that influence the levels of age-sensitive T-cell subsets. Some of these QTL have effects that are demonstrable in young-adult mice (8 months of age) and others demonstrable only in middle-aged mice (18 months). Biomarker studies show that T-cell subset levels measured at 8 or 18 months are significant predictors of lifespan for mice dying of lymphoma, fibrosarcoma, mammary adenocarcinoma, or all causes combined. Mice whose immune systems resemble that of young animals, i.e. with low levels of CD4 + and CD8 + memory T cells and relatively high levels of CD4 + T cells, tend to outlive their siblings with the opposite subset pattern. Biochemical analyses show that T cells from aged mice show defects in the activation process within a few minutes of encountering a stimulus and that the defects precede the recognition by the T-cell receptor of agonist peptides on the antigen-presenting cell. Defective assembly of cytoskeletal fibers and hyperglycosylation of T-cell surface glycoproteins contribute to the immunodeficiency state, and indeed treatment with a sialylglycoprotein endopeptidase can restore full function to CD4 + T cells from aged donors in vitro .